Author

Defense Date

2011

Document Type

Thesis

Degree Name

Master of Science

Department

Microbiology & Immunology

First Advisor

Masoud Manjili

Abstract

In patients undergoing hematopoietic stem cell transplantation (HSCT) with HLA-identical donors, genetic polymorphisms result in a mismatch between donors and recipients in their minor histocompatibility antigens (mHAgs), and tumors may also express tumor-associated antigens (TAA) that may not be abundantly present in the donors. Donor T cells can recognize such mHAgs and TAAs as foreign antigens and generate an objective response against hematologic malignancies in a graft-versus-tumor (GVT) effect. However, a major side effect of HSCT occurs when donor T cells are alloreactive against the recipients’ normal cells, leading to graft-versus-host disease (GVHD). The ability to identify T cell clones that are exclusively involved in the GVT or GVHD responses remains elusive. In this study, we looked at clonally-driven CD3+ T cells in patients with hematologic malignancies prior to and after transplantation. We identified Vbeta families of increased expression involved in GVHD or GVT responses, with Vbetas 4, 11, and 23 being associated with GVHD, Vbetas 9, 16, and 20 being associated with GVT, and Vbetas 2, 3, 7, 8, 12, 15, and 17 being involved in GVHD and/or GVT. We were also able to identify some of the Vbeta families that were increased in the peripheral blood at the site of GVHD. Furthermore, one of our twelve patients had donor lymphocyte infusions (DLIs) for treatment of relapse, from which we were able to observe oligoclonal T cells that emerged at the time of post-DLI remission and re-establishment of GVHD.